Gene therapy is a treatment strategy that rests on providing a normal copy of cDNA to affected tissues to compensate for the mutated gene. Cystic Fibrosis is a very common inherited lethal disorder in which secretory epithelia and tissues become progressively obstructed by abnormal secretions. Most of the morbidity and mortality in CF arises from lung disease. The anatomy and histology of the respiratory tract allow the delivery of a gene therapy by direct instillation to the airways or by inhalation of an aerosol. The CF Gene Therapy Center at the Johns Hopkins University School of Medicine is developing the adeno-associated virus vector for the purpose of producing high frequency, stable transduction and expression of the normal CFTR cDNA in the CF airways. The JHU CF group together with Targeted Genetics Corporation have been able to generate high titer AAV-CFTR, free of wild type AAV or adenovirus, containing only the transgene and no viral coding sequences. The hypothesis of this project is that AAV-CFTR vector administration will result in recombinant human CFTR mRNA and protein expression and normalization of nasal epithelial potential difference in adult CF patients with mild lung disease at a vector dose which results in minimal or no toxicity. The specific aims are: 1) To assess safety of a single dose of AAV-CFTR to the nasal epithelium and the superior segment of the right lower lobe by dose escalation, and to identify the maximum tolerated dose (MTD); 2) To assess AAV-CFTR-mediated gene transfer in vivo; 3) To assess CFTR gene expression and function; 4) To assess the clinical impact of CFTR gene transfer; 5) To monitor the patient immune response against CFTR or the vector capsid. This is a two center, Phase I randomized, double-blind, placebo-controlled, dose escalation study originally designed for 16 patients, amended for 19, and planned to complete at an n=27 as the dose is increased through 4 higher logs. Each patient is randomized to receive a single dose of AAV-CFTR or vehicle administered to the right or left nasal epithelium and a single dose of open-label AAV-CFTR vector to the superior segment of the right lower lobe. The doses range from 3 x 101 RU through 1 x 109 RU. In addition to safety studies and viral cultures of blood, sputum, bronchoalveolar lavage fluid, urine, and nasal lavage fluid, DNA PCR, RT-PCR, and nasal potential differences are performed at intervals at baseline and following dose administration. Descriptive statistics will be used to summarize changes from baseline in the measured parameters for each dose cohort. Future directions upon successful completion of this study will be a phase I study of single dose AAV-CFTR delivery by aerosol, and a study of the safety and efficacy of repeat dosing by aerosol. The close proximity of the basic research efforts of the CF Research Development Program, the CF Gene Therapy Center, and CF Clinical Care Center at the JHU School of Medicine provide a dynamic and supportive environment for the execution of this Phase I gene therapy clinical protocol.